US4914127A - 3-Demethylmevalonic acid derivatives, a process for their preparation pharmaceutical products based on these compounds, their use and intermediates - Google Patents

3-Demethylmevalonic acid derivatives, a process for their preparation pharmaceutical products based on these compounds, their use and intermediates Download PDF

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US4914127A
US4914127A US07/320,924 US32092489A US4914127A US 4914127 A US4914127 A US 4914127A US 32092489 A US32092489 A US 32092489A US 4914127 A US4914127 A US 4914127A
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compounds
formula
aromat
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Gerhard Beck
Bela Kerekjarto
Hans-Hermann Lau
Gunther Wess
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Hoechst AG
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Hoechst AG
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Priority claimed from DE19863615446 external-priority patent/DE3615446A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5456—Arylalkanephosphonium compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to new synthetic analogs of "Compactin" of the general formula I ##STR2## in the form of the ⁇ -lactone depicted in the formula I or in the form of the dihydroxy acid derivative Ia.
  • "Compactin" of the general formula I ##STR2## in the form of the ⁇ -lactone depicted in the formula I or in the form of the dihydroxy acid derivative Ia.
  • A-B denotes a radical of the formula --CH ⁇ CH-- or --CH 2 --CH 2 --,
  • Z denotes a --CH 2 -- or --CH 2 --CH 2 -- group
  • R 1 denotes a cycloaliphatic hydrocarbon radical which has 3 to 7 carbon atoms and is optionally substituted with 1 or 2 methyl groups, denotes a phenyl radical which can be substituted in the nucleus 1-3 times by halogen, trifluoromethyl, alkyl or alkoxy, each having 1-6 carbon atoms, or by hydroxymethyl, or denotes a furyl, thienyl or pyridyl radical, it being possible for the heteroaromatic radicals to be substituted 1-2 times by halogen, trifluoromethyl, alkyl or alkoxy, each having 1-6 carbon atoms,
  • R 2 and R 3 denote hydrogen, halogen, trifluoromethyl, alkyl or alkoxy, each having 1-6 carbon atoms,
  • R 4 denotes hydrogen or a straight-chain or branched C 1 -C 5 -alkyl radical, benzyl, benzyl which is substituted 1-2 times by C 1 -C 4 -alkyl or denotes halogen, alkali metal or ammonium (NH4.sup. ⁇ ) or ammonium ion which is substituted with C 1 -C 4 -alkyl or hydroxy-C 1 -C 4 -alkyl.
  • the invention relates to the pure enantiomers having the absolute configuration 4R,6S which is indicated in the general formula I, the open-chain carboxylic acids and esters and salts having the absolute configuration 3R,5S.
  • Cyclopentyl, cyclohexyl, or a phenyl radical which can be substituted in the nucleus 1-3 times by halogen, trifluoromethyl, hydroxymethyl, or alkyl or alkoxy having 1 to 4 carbon atoms, a furyl, thienyl or pyridyl radical, it being possible for the heteroaromatic radicals to be substituted 1-2 times by halogen, trifluoromethyl, or alkyl or alkoxy having 1 to 4 carbon atoms.
  • the invention furthermore relates to a process for the preparation of compounds of the formulaie I and Ia, which comprises:
  • the chiral aldehyde of the formula III which is used as starting material in the process according to the invention is obtained by a process known from the literature (Yuh Lin, J. R. Falck, Tetrahedron Letters 23, 4305-4308 (1982)) from the corresponding alcohol by oxidation with, for example, CrO 3 .
  • the methyl acetal protective group in the compounds of the formula IV can be selectively eliminated in the generally customary manner by acid hydrolysis, preferably using a mixture of glacial acetic acid, tetrahydrofuran and water in the ratio 3:2:2 at +20° to +90° C. in 6-24 hours.
  • the oxidation of the compounds of the formula V to give a lactone of the formula VI can be carried out by oxidizing agents such as CrO 3 x2Pyr, or pyridinium chlorochromate in inert solvents such as, for example, methylene chloride or chloroform.
  • oxidizing agents such as CrO 3 x2Pyr, or pyridinium chlorochromate in inert solvents such as, for example, methylene chloride or chloroform.
  • Another possibility for the oxidation comprises reaction with thioanisole/Cl 2 /NEt 3 in carbon tetrachloride, or reaction with DMSO/oxalyl chloride/NEt 3 at -20° C.
  • the protective group R 5 in the compounds of the formula VI is eliminated. This can take place with strong acids, such as 5-normal hydrochloric acid or sulfuric acid at -10° to +30° C., or with fluoride ions, preferably by dissolving the compounds of the formula VI in tetrahydrofuran or diethyl ether and adding a mixtue of tetrabutylammonium fluoride and glacial aceticacid followed by stirring at 0° C. to 40° C. for between 1 and 12 hours.
  • strong acids such as 5-normal hydrochloric acid or sulfuric acid at -10° to +30° C.
  • fluoride ions preferably by dissolving the compounds of the formula VI in tetrahydrofuran or diethyl ether and adding a mixtue of tetrabutylammonium fluoride and glacial aceticacid followed by stirring at 0° C. to 40° C. for between 1 and 12 hours.
  • the compounds of the formula I are obtained in optically pure form.
  • Compounds of the formula I in the form of the ⁇ -lactone can be hydrolyzed in an alkaline medium to give the corresponding salts of the dihydroxy acids, for example using NaOH or kOH in a low molecular weight alcohol such as methanol, or in ethers such as dimethoxyethane or THF, where appropriate in the presence of water.
  • the alkali metal cation in the resulting salts of the dihydroxy acids can be replaced by any desired cations after acidification in ion exchangers in the customary manner.
  • the dihydroxy acids are allowed to run through a column packed with a cation exchanger such as, for example, one based on polystyrene/divinylbenzene (®Amberlite CG-150 or ®Dowex-CCR-2).
  • a cation exchanger such as, for example, one based on polystyrene/divinylbenzene (®Amberlite CG-150 or ®Dowex-CCR-2).
  • the cation exchanger is loaded with the desired cation, for example with ammonium ions derived from a primary, secondary or tertiary amine.
  • the desired salt is obtained by evaporating the eluate.
  • Ammonium salts of the dihydroxy acids which are derived from a primary, secondary or tertiary amine, can also be prepared by addition of an equimolar amount of the appropriate amine to the free dihydroxy acids in an alcoholic solution, and evaporation of the solvent.
  • the free dihydroxy acids Ia of the ⁇ -lactones I can be esterified by customary methods, for exmple using a diazoalkane.
  • a diazoalkane for exmple using a diazoalkane.
  • the resulting esters can be isolated in a straightforward manner by evaporation of the solvent and, where appropriate, can be purified by chromatography.
  • Another method of esterification comprises reacting salts of the dihydroxy acids Ia in the presence of a base, such as, for example, a metal alcoholate or metal carbonate, in a suitable solvent, with an alkylating agent.
  • a base such as, for example, a metal alcoholate or metal carbonate
  • suitable solvents are alcohols such as, for example, methanol or tert.-butanol, ethers such as tetrahydrofuran or 1,2-dimethoxyethane and, in particular, dipolar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidone.
  • the method of transesterification with an excess of alcohols such as, for example, methanol, ethanol or isopropanol is also suitable for the preparation of esters of the dihydroxy acids.
  • aldehyde of the formula III is not in the form of the pure enantiomer it is also possible for mixtures of the anantiomeric final products to be produced, which can be separated by generally customary processes.
  • the HMG-CoA reductase activity was measured on solubilized enzyme preparations from liver microsomes of rats which, after the day/night rhythm had been changed, were induced with cholestyramine (®Cuemid).
  • the substrate used was (S,R) 14 C-HMG-CoA, and the concentration of NADPH was maintained during the incubation by a regenerating system.
  • 14 C-Mevalonate was removed from the substrate and other products (for example 14 C-HMG) by column elution, the elution profile for each individual sample being determined. Constant inclusion of 3 H-mevalonate was dispensed with because the determination was of the relative inhibitory effect.
  • Monolayers of fibroblasts (L cells) in lipoprotein-free nutrient medium were incubated with appropriate concentrations of test substances for a specified period (for example 3 hours) and then the HMG-CoA reductase activity of the cells was determined by modification of the method of Chang et al. (J. Biol. Chem. 256, 6174 (1981)).
  • the cell extracts were incubated with D,L-[ 3 H]-HMG-CoA, and the product [ 3 H]-mevalonate formed from the cells by the action of the HMG-CoA reductase activity present was, after cyclization to [ 3 H]-mevalonolactone, separated from the starting material by thin-layer chromatography and, by use of an internal standard of [ 14 C]-mevalonate, the amount of [ 3 H]-mevalonate formed in unit time was determined and related to the amount of cellular protein.
  • the HMG-CoA reductase activity in the cell culture found on addition of a specified concentration of a test product was related, as the percentage, to that of a culture treated in the same way without the test product but with the same solvent concentration. ##STR20##
  • the following figures for the inhibition of HMG-CoA reductase were determined for the compounds according to the invention, for example (the IC 50 (M) is that concentration of the compound which brings about 50% inhibition of HMG-CoA reductase activity):
  • the compounds of the general formula I or Ia are distinguished by potent inhibition of HMG-CoA reductase, the rate-determining enzyme of cholesterol biosynthesis.
  • HMG-CoA reductase is widespread in nature. It catalyzes the formation of mevalonic acid from HMG-CoA. This reaction is a central step in cholesterol biosynthesis (cf. J. R. Sabine in CRC Series in Enzyme Biology: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase, CRC Press Inc. Boca Raten, Fla. 1983 (ISBN 0-8493-6551-1)).
  • High cholesterol levels are regarded as being connected with a number of diseases such as, for example, coronary heart diseases or arteriosclerosis. Hence the reduction of elevated cholesterol levels is an aim of therapy for the prevention and treatment of diseases of this type.
  • Inhibitors of HMG-CoA reductase block cholesterol biosynthesis at an early stage.
  • the compounds of the general formula I and Ia are suitable as hypolipidemics and for the treatment and prophylaxis of arteriosclerotic changes.
  • the invention also relates to pharmaceutical products based on these compounds and their use as medicaments, in particular as hypolipidemics and for the prophylaxis of arteriosclerotic changes.
  • hypolipidemics or antiarteriosclerotics employs oral doses from 3 to 2,500 mg, but preferably in the dose range 10-500 mg. These daily doses can, as required, also be divided into two to four single doses or administered in controlled release form. The dosage regimen may depend on the type, age, weight, sex and medical condition of the patient.
  • An additional cholesterol-lowering effect can be achieved by administration of the compounds according to the invention concurrently with substances which bind bile acids, such as, for example, anion exchanger resins.
  • the increased excretion of bile acids results in an enhancement of new synthesis and thus in an increase in cholesterol degradation (cf. M. S. Brown, P. T. Koranen and J. C. Goldstein Science 212, 628 (1981); M.S. Brown, J. C. Goldstein Spektrum dermaschine 1985, 1, 96).
  • the compounds according to the invention, of the formula I and Ia can be used in the form of the ⁇ -lactones, as the free acids, or in the form of their physiologically acceptable inorganic or organic salts or as esters.
  • Acids and salts or esters can be used in the form of their aqueous solutions or suspensions or dissolved or suspended in pharmacologically acceptable organic solvents such as mono- or polyhydric alcohols such as, for example, ethanol, ethylene glycol or glycerol, in triacetin, in alcohol/acetaldehyde diacetal mixtures, oils such as, for example, sunflower oil or fish liver oil, ethers such as, for example, diethylene glycol dimethyl ether or polyethers such as, for example, polyethylene glycol, or in the presence of other pharmacologically acceptable polymeric vehicles such as, for example, polyvinylpyrrolidone or in solid formulations.
  • pharmacologically acceptable organic solvents such as mono- or polyhydric alcohols such as, for
  • Solid presentations which can be administered orally and contain the customary auxiliaries are preferred for the compounds of the formula I and Ia. They are prepared by customary methods.
  • Tablets, coated tablets or capsules are particularly suitable as formulations for oral use.
  • a dosage unit preferably contains 10 to 500 mg of active compound.
  • the compounds of the formulae II, III, IV, V and VI are new and represent valuable intermediates for the preparation of compounds of the formula I. Hence the invention also relates to these compounds and to processes for their preparation.
  • Rf 0.57 mobile phase: cyclohexane/ethyl acetate 1:1.

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  • Urology & Nephrology (AREA)
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  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
US07/320,924 1985-08-29 1989-03-08 3-Demethylmevalonic acid derivatives, a process for their preparation pharmaceutical products based on these compounds, their use and intermediates Expired - Fee Related US4914127A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19853530797 DE3530797A1 (de) 1985-08-29 1985-08-29 3-desmethyl-mevalonsaeurederivate, verfahren zu ihrer herstellung pharmazeutische praeparate auf basis dieser verbindungen, ihre verwendung sowie zwischenprodukte
DE3530797 1985-08-29
DE19863615446 DE3615446A1 (de) 1986-05-07 1986-05-07 3-desmethyl-mevalonsaeurederivate, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen, ihrer verwendung sowie zwischenprodukte
DE3615446 1986-05-07

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US (1) US4914127A (pt)
EP (1) EP0217092B1 (pt)
JP (1) JPH0830027B2 (pt)
KR (1) KR870002114A (pt)
AR (1) AR242206A1 (pt)
AU (1) AU583943B2 (pt)
CA (1) CA1294284C (pt)
DE (1) DE3669874D1 (pt)
DK (1) DK169127B1 (pt)
ES (1) ES2001595A6 (pt)
FI (1) FI90868C (pt)
GR (1) GR862210B (pt)
HU (1) HU195799B (pt)
IE (1) IE59312B1 (pt)
IL (1) IL79855A0 (pt)
NO (1) NO171108C (pt)
PT (1) PT83269B (pt)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5470982A (en) * 1988-01-20 1995-11-28 Bayer Aktiengesellschaft Disubstituted pyridines
US9029606B2 (en) 2011-06-27 2015-05-12 Sumitomo Chemical Company, Limited Method for producing 2-chloromethylbenzaldehyde, 2-chloromethylbenzaldehyde-containing composition, and method for storing same

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4789682A (en) * 1987-03-17 1988-12-06 Merck & Co., Inc. Antihypercholesterolemic compounds
DE3722809A1 (de) * 1987-07-10 1989-01-19 Hoechst Ag 3-desmethyl-4-fluor-mevalonsaeurederivate, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen, ihre verwendung und zwischenprodukte
US4863957A (en) * 1987-12-21 1989-09-05 Rorer Pharmaceutical Corporation Novel HMG-CoA reductase inhibitors
FR2669031A1 (fr) * 1990-11-09 1992-05-15 Rhone Poulenc Sante Procede de preparation de derives du tetrahydropyranne.
US5840620A (en) * 1994-06-15 1998-11-24 Seager; Carleton H. Method for restoring the resistance of indium oxide semiconductors after heating while in sealed structures
CN101570510B (zh) * 2008-04-30 2011-08-31 上海医药工业研究院 喹啉类化合物及其药物组合物、制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4440927A (en) * 1981-06-19 1984-04-03 Merck & Co., Inc. Process for preparing inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase via a chiral synthon
EP0164049A2 (en) * 1984-06-04 1985-12-11 Merck & Co. Inc. Process for preparing HMG-CoA reductase inhibtors with a 3,5-dihydroxypentanoate subunit
US4588715A (en) * 1984-06-04 1986-05-13 Sandoz, Inc. Heptenoic acid derivatives
US4622338A (en) * 1985-03-11 1986-11-11 G. D. Searle & Co. Substituted glutaric acid lactones in the treatment of hyperlipidemia
US4710513A (en) * 1979-08-17 1987-12-01 Merck & Co., Inc. Substituted pyranone inhibitors of cholesterol synthesis
EP0680038A2 (fr) * 1994-04-28 1995-11-02 Commissariat A L'energie Atomique Dispositif de contrôle de la position et/ou de la focalisation d'un faisceau lumineux focalisé

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710513A (en) * 1979-08-17 1987-12-01 Merck & Co., Inc. Substituted pyranone inhibitors of cholesterol synthesis
US4440927A (en) * 1981-06-19 1984-04-03 Merck & Co., Inc. Process for preparing inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase via a chiral synthon
EP0164049A2 (en) * 1984-06-04 1985-12-11 Merck & Co. Inc. Process for preparing HMG-CoA reductase inhibtors with a 3,5-dihydroxypentanoate subunit
US4588715A (en) * 1984-06-04 1986-05-13 Sandoz, Inc. Heptenoic acid derivatives
US4622338A (en) * 1985-03-11 1986-11-11 G. D. Searle & Co. Substituted glutaric acid lactones in the treatment of hyperlipidemia
EP0680038A2 (fr) * 1994-04-28 1995-11-02 Commissariat A L'energie Atomique Dispositif de contrôle de la position et/ou de la focalisation d'un faisceau lumineux focalisé

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chemical Abstract No. 99: 38364d, 1983. *
Stokker et al., "3-Hydroxy-3-methylglutaryl-etc", J. Med. Chem., (1986), 29, 170-181.
Stokker et al., 3 Hydroxy 3 methylglutaryl etc , J. Med. Chem., (1986), 29, 170 181. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5470982A (en) * 1988-01-20 1995-11-28 Bayer Aktiengesellschaft Disubstituted pyridines
US9029606B2 (en) 2011-06-27 2015-05-12 Sumitomo Chemical Company, Limited Method for producing 2-chloromethylbenzaldehyde, 2-chloromethylbenzaldehyde-containing composition, and method for storing same

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NO171108B (no) 1992-10-19
FI90868B (fi) 1993-12-31
IL79855A0 (en) 1986-11-30
AR242206A1 (es) 1993-03-31
IE59312B1 (en) 1994-02-09
NO863461L (no) 1987-03-02
ES2001595A6 (es) 1988-06-01
PT83269B (pt) 1989-05-12
KR870002114A (ko) 1987-03-30
PT83269A (de) 1986-09-01
FI863471A0 (fi) 1986-08-27
EP0217092A2 (de) 1987-04-08
GR862210B (en) 1986-12-23
FI863471A (fi) 1987-03-01
FI90868C (fi) 1994-04-11
IE862302L (en) 1987-02-28
NO863461D0 (no) 1986-08-28
DE3669874D1 (de) 1990-05-03
NO171108C (no) 1993-01-27
EP0217092B1 (de) 1990-03-28
HU195799B (en) 1988-07-28
HUT41757A (en) 1987-05-28
DK409986D0 (da) 1986-08-28
AU583943B2 (en) 1989-05-11
JPH0830027B2 (ja) 1996-03-27
DK409986A (da) 1987-03-01
JPS6251641A (ja) 1987-03-06
DK169127B1 (da) 1994-08-22
EP0217092A3 (en) 1987-06-16
CA1294284C (en) 1992-01-14
AU6202886A (en) 1987-03-05

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